An increasing number of reports on the biological activity of gold(I) and gold(III) complexes have brought to light their capacity to act against solid tumors. However, there is a gap in understanding the plausible mechanisms by which gold compounds act as antitumor agents. The long-term goal of this proposal is the development of novel gold-derived anticancer chemotherapeutics that can overcome some of the drawbacks associated with the use of current platinum drugs. Our hypothesis is that by varying the oxidation state and coordination geometry of the gold derivatives we can modulate and improve their activity as anti-tumor agents. These complexes may prove to be effective antitumor agents acting through different mechanisms than those of cisplatin. Some of the effects of existing gold compounds in vitro appear to be a consequence of direct interference with redox-dependent mitochondrial functions (inhibition of mitochondrial enzymes) instead of binding and damaging DNA but mechanistic data is limited. We will synthesize stable gold compounds with different oxidation states and varying ligand coordination geometries. Subsequently, the cytotoxicity profiles and mechanism of action of gold derivatives will be evaluated in different cancer cell lines. Our specific aims are: (1) Synthesis of gold(I) and gold(III) compounds with pincer phosphorus containing ligands, (2) Study of the cytotoxic/apoptotic properties against human cancer cell lines in vitro, stability, and mechanism of action of the gold-derived compounds. This second aim contains three well-defined research objectives: A) In vitro evaluation of the cytotoxicity profiles of the gold derived compounds against selected cell lines. B) Study of the stability of the compounds in vitro by 31P NMR under biologically relevant conditions. C) Elucidation of the mechanism of action of gold derived cytotoxic compounds. The study of the interaction of selected compounds with DNA and mitochondrial proteins will shed light on the possible mechanisms of action of gold compounds with the same set of ligands and in different oxidation states. A systematic study of the effects of gold compounds in different oxidation states on mitochondrial functions will be subsequently undertaken. An extra innovative approach in this application is that the set of ligands chosen to be coordinated to the gold centers allows the preparation of gold compounds in different oxidation states (I and III) as well as the preparation of bimetallic gold complexes. This will allow a comparative study of oxidation state versus biological activity as well as the study of synergist biological effects caused by more than one metallic centre. Thus, the proposed research is relevant to that part of NIH's mission in the cure of human diseases by developing novel pharmaceuticals as possible alternatives to antitumor platinum chemotherapeutics. PUBLIC HEALTH RELEVANCE: The proposed studies are important since they will help to design new anticancer pharmaceuticals by understanding the mechanism of action of gold compounds. This has relevance to public health, because of the clinical problems associated to the drugs currently used. Thus, the findings are ultimately expected to be applicable to the health of human beings.